2,4-disubstituted pyrimidine derivative, preparation method therefor and use thereof
View Patent ↗The present invention belongs to the field of chemical medicines, and particularly relates to a 2,4-disubstituted pyrimidine derivative, a preparation method therefor and a use thereof. The present invention provides a 2,4-disubstituted pyrimidine derivative, the structural formula of which is as shown in formula I. The present invention also provides a preparation method for the 2,4-disubstituted pyrimidine derivative and a use thereof. The 2,4-disubstituted pyrimidine derivative provided by the present invention can be used as a kinase inhibitor with double functional targets of JAK2 and FLT3, or a kinase inhibitor with independent functional targets of JAK2 or FLT3, thus providing a new choice for preparing a multi-target inhibitor.
1. A 2,4-disubstituted pyrimidine derivative, the structural formula of which is as shown in Formula I:
Formula I
wherein, Q is CH; Z 2 and Z 3 are, independently of one another N; Z 1 is C-R 8 ; and Z 4 is C-R 8 or
R 6 is C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl;
R 8 , R 9 are, independently of one another, —H or C 1 -C 10 alkyl;
R 1 , R 2 and R 5 are, independently of one another, —H, halogen or C 1 -C 10 alkyl;
R 3 is
n=0-4 and p=0-4;
R 4 is —H, halogen or C 1 -C 10 alkoxy;
R 11 is
or hydroxyl-substituted C 1 -C 10 alkyl; q=0-4;
R 12 is —H, C 1 -C 10 alkoxy or hydroxyl-substituted C 1 -C 10 alkyl;
R 15 and R 16 are, independently of one another, —H, substituted or unsubstituted C 1 -C 10 alkyl or
and a substituent of the substituted C 1 -C 10 alkyl is —OH, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl,
R 18 is —OH; and b=0-6; and
R 19 is C 1 -C 10 alkyl.
2. The 2,4-disubstituted pyrimidine derivative according to claim 1 , wherein R 6 is C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
3. The 2,4-disubstituted pyrimidine derivative according to claim 1 , wherein R 8 and R 9 are, independently of one another, —H or C 1 -C 8 alkyl.
4. The 2,4-disubstituted pyrimidine derivative according to claim 1 , wherein R 1 , R 2 and R 5 are, independently of one another, —H, halogen or C 1 -C 8 alkyl.
5. The 2,4-disubstituted pyrimidine derivative according to claim 1 , wherein:
R 3 is
R 4 is —H, halogen or C 1 -C 8 alkoxy;
n=0-3; and
p=0-3.
6. The 2,4-disubstituted pyrimidine derivative according to claim 5 , wherein the
is
7. The 2,4-disubstituted pyrimidine derivative according to claim 1 , wherein:
R 11 is
or hydroxyl-substituted C 1 -C 8 alkyl; and q=0-3; and
R 12 is —H, C 1 -C 8 alkyl or hydroxyl-substituted C 1 -C 8 alkyl.
8. The 2,4-disubstituted pyrimidine derivative according to claim 1 , wherein:
R 15 and R 16 are, independently of one another, —H, substituted or unsubstituted C 1 -C 8 alkyl or
a substituent of the substituted C 1 -C 8 alkyl is —OH, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl,
R 18 is —OH; R 19 is C 1 -C 8 alkyl; and b=0-5.
9. The 2,4-disubstituted pyrimidine derivative according to claim 1 , the structural formula of which is as shown in Formula II:
wherein, R 1 , R 2 and R 5 are, independently of one another, —H, halogen or C 1 -C 10 alkyl;
R 3 is
R 4 is —H, halogen or C 1 -C 10 alkoxy; n=0-4; and p=0-4;
R 11 is
or hydroxyl-substituted C 1 -C 10 alkyl; and q=0-4;
R 12 is —H, C 1 -C 10 alkyl or hydroxyl-substituted C 1 -C 10 alkyl;
R 15 and R 16 are, independently of one another, —H, substituted or unsubstituted C 1 -C 10 alkyl or
and a substituent of the substituted C 1 -C 10 alkyl is —OH, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl,
R 18 is —OH; and b=0-6; and
R 19 is C 1 -C 10 alkyl.
10. The 2,4-disubstituted pyrimidine derivative according to claim 9 , wherein R 1 , R 2 and R 5 are, independently of one another, —H, halogen or C 1 -C 8 alkyl.
11. The 2,4-disubstituted pyrimidine derivative according to claim 9 , wherein:
R 3 is
R 4 is —H, halogen or C 1 -C 8 alkoxy; n=0-3; and p=0-3.
12. The 2,4-disubstituted pyrimidine derivative according to claim 11 , wherein the
is
13. The 2,4-disubstituted pyrimidine derivative according to claim 9 , wherein:
R 11 is
or hydroxyl-substituted C 1 -C 8 alkyl; and q=0-3; and
R 12 is —H, C 1 -C 8 alkyl or hydroxyl-substituted C 1 -C 8 alkyl.
14. The 2,4-disubstituted pyrimidine derivative according to claim 9 , wherein:
R 15 and R 16 are, independently of one another, —H, substituted or unsubstituted C 1 -C 8 alkyl or
a substituent of the substituted C 1 -C 8 alkyl is —OH, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl,
R 18 is —OH; R 19 is C 1 -C 8 alkyl; and b=0-5.
15. The 2,4-disubstituted pyrimidine derivative according to claim 9 , the structural formula of which is as shown in Formula IV:
wherein, R 1 is halogen or C 1 -C 4 alkyl; and R 4 is —H, halogen or C 1 -C 4 alkoxy; and
R 15 and R 16 are, independently of one another, —H, substituted or unsubstituted C 1 -C 10 alkyl
or
a substituent of the substituted C 1 -C 10 alkyl is —OH, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl,
R 18 is —OH; b=0-6; and R 19 is C 1 -C 10 alkyl.
16. The 2,4-disubstituted pyrimidine derivative according to claim 15 , wherein R 1 is —F, or methoxyl; and R 4 is —H, —F or methoxyl.
17. The 2,4-disubstituted pyrimidine derivative according to claim 15 , wherein R 15 and R 16 are, independently of one another, —H, substituted or unsubstituted C 1 -C 8 alkyl or
a substituent of the substituted C 1 -C 8 alkyl is —OH, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl,
R 18 is —OH; R 19 is C 1 -C 8 alkyl; and b=0-5.
18. The 2,4-disubstituted pyrimidine derivative according to claim 9 , the structural formula of which is as shown in Formula V:
wherein, R 12 is —H, C 1 -C 10 alkyl or hydroxyl-substituted C 1 -C 10 alkyl.
19. The 2,4-disubstituted pyrimidine derivative according to claim 18 , wherein R 12 is —H, C 1 -C 8 alkyl or hydroxyl-substituted C 1 -C 8 alkyl.
20. A 2,4-disubstituted pyrimidine derivative, the structural formula of which is as shown below:
21. A pharmaceutically acceptable salt of the 2,4-disubstituted pyrimidine derivative according to claim 1 , wherein said pharmaceutically acceptable salt further comprises at least one of p-toluene sulfonate, oxalate, citrate, malate, salicylate, tartrate, phosphate, methanesulfonate, sulfate, fumarate, hydrochloride and maleate.
22. A pharmaceutically acceptable hydrate of the 2,4-disubstituted pyrimidine derivative according to claim 1 .
23. A pharmaceutical composition comprising: the 2,4-disubstituted pyrimidine derivative according to claim 1 , a salt of the 2,4-disubstituted pyrimidine derivative or a hydrate of the 2,4-disubstituted pyrimidine derivative; and a pharmaceutically acceptable auxiliary ingredient.
24. A method of inhibiting JAK2 comprising administering the pharmaceutical composition according to claim 23 to a subject in need of JAK2 inhibition.
25. A method of inhibiting FLT3 comprising administering the pharmaceutical composition according to claim 23 to a subject in need of FLT3 inhibition.
26. A method of treating a tumor comprising administering to a subject the pharmaceutical composition according to claim 23 , wherein the tumor is a hematological tumor, and the subject suffers from acute myeloid leukemia, myelodysplastic disorder, or myelofibrosis.
27. A method for treating essential thrombocythemia comprising administering to a subject the pharmaceutical composition according to claim 23 .